@article{RascheKumarGershneretal.2019,
  author    = {Rasche, Leo and Kumar, Manoj and Gershner, Grant and Samant, Rohan and Van Hemert, Rudy and Heidemeier, Anke and Lapa, Constantin and Bley, Thorsten and Buck, Andreas and McDonald, James and Hillengass, Jens and Epstein, Joshua and Thanendrarajan, Sharmilan and Schinke, Carolina and van Rhee, Frits and Zangari, Maurizio and Barlogie, Bart and Davies, Faith E. and Morgan, Gareth J. and Weinhold, Niels},
  title     = {Lack of Spleen Signal on Diffusion Weighted MRI is associated with High Tumor Burden and Poor Prognosis in Multiple Myeloma: A Link to Extramedullary Hematopoiesis?},
  series = {Theranostics},
  volume    = {9},
  journal   = {Theranostics},
  number    = {16},
  doi       = {10.7150/thno.33289},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224982},
  pages     = {4756-4763},
  year      = {2019},
  abstract  = {Due to the low frequency of abnormalities affecting the spleen, this organ is often overlooked during radiological examinations. Here, we report on the unexpected finding, that the spleen signal on diffusion-weighted MRI (DW-MRI) is associated with clinical parameters in patients with plasma cell dyscrasias. Methods: We investigated the spleen signal on DW-MRI together with clinical and molecular parameters in 295 transplant-eligible newly diagnosed Multiple Myeloma (NDMM) patients and in 72 cases with monoclonal gammopathy of undetermined significance (MGUS). Results: Usually, the spleen is the abdominal organ with the highest intensities on DW-MRI. Yet, significant signal loss on DW-MRI images was seen in 71 of 295 (24\%) NDMM patients. This phenomenon was associated with the level of bone marrow plasmacytosis (P=1x10(-10)) and International Staging System 3 (P=0.0001) but not with gain(1q), and del(17p) or plasma cell gene signatures. The signal was preserved in 72 individuals with monoclonal gammopathy of undetermined significance and generally re-appeared in MM patients responding to treatment, suggesting that lack of signal reflects increased tumor burden. While absence of spleen signal in MM patients with high risk disease defined a subgroup with very poor outcome, re-appearance of the spleen signal after autologous stem cell transplantation was seen in patients with improved outcome. Our preliminary observation suggests that extramedullary hematopoiesis in the spleen is a factor that modifies the DW-MRI signal of this organ. Conclusions: The DW-MRI spleen signal is a promising marker for tumor load and provides prognostic information in MM.},
  language  = {en}
}
@article{RascheKortuemRaabetal.2019,
  author    = {Rasche, Leo and Kort{\"u}m, K. Martin and Raab, Marc S. and Weinhold, Niels},
  title     = {The impact of tumor heterogeneity on diagnostics and novel therapeutic strategies in multiple myeloma},
  series = {International Journal of Molecular Sciences},
  volume    = {20},
  journal   = {International Journal of Molecular Sciences},
  number    = {5},
  issn      = {1422-0067},
  doi       = {10.3390/ijms20051248},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285402},
  year      = {2019},
  abstract  = {Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical impact of these two types of tumor heterogeneity. Target mutations are often dominant at one site but absent at other sites, which poses a significant challenge to personalized therapy in myeloma. The same holds true for high-risk subclones, which can be locally restricted, and as such not detectable at the iliac crest, which is the usual sampling site. Imaging can improve current risk classifiers and monitoring of residual disease, but does not allow for deciphering the molecular characteristics of tumor clones. In the era of novel immunotherapies, the clinical impact of heterogeneity certainly needs to be re-defined. Yet, preliminary observations indicate an ongoing impact of spatial heterogeneity on the efficacy of monoclonal antibodies. In conclusion, we recommend combining molecular tests with imaging to improve risk prediction and monitoring of residual disease. Overcoming intra-tumor heterogeneity is the prerequisite for curing myeloma. Novel immunotherapies are promising but research addressing their impact on the spatial clonal architecture is highly warranted.},
  language  = {en}
}
@article{JanjetovicLohneisNogaietal.2021,
  author    = {Janjetovic, Snjezana and Lohneis, Philipp and Nogai, Axel and Balci, Derya and Rasche, Leo and J{\"a}hne, Doris and Bokemeyer, Carsten and Schilling, Georgia and Blau, Igor Wolfgang and Schmidt-Hieber, Martin},
  title     = {Clinical and biological characteristics of medullary and extramedullary plasma cell dyscrasias},
  series = {Biology},
  volume    = {10},
  journal   = {Biology},
  number    = {7},
  issn      = {2079-7737},
  doi       = {10.3390/biology10070629},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242592},
  year      = {2021},
  abstract  = {Background: Extramedullary plasma cell (PC) disorders may occur as extramedullary disease in multiple myeloma (MM-EMD) or as primary extramedullary plasmocytoma (pEMP)/solitary osseous plasmocytoma (SOP). In this study, we aimed to obtain insights into the molecular mechanisms of extramedullary spread of clonal PC. Methods: Clinical and biological characteristics of 87 patients with MM-EMD (n = 49), pEMP/SOP (n = 20) and classical MM (n = 18) were analyzed by using immunohistochemistry (CXCR4, CD31, CD44 and CD81 staining) and cytoplasmic immunoglobulin staining combined with fluorescence in situ hybridization (cIg-FISH). Results: High expression of CD44, a cell-surface glycoprotein involved in cell-cell interactions, was significantly enriched in MM-EMD (90\%) vs. pEMP/SOP (27\%) or classical MM (33\%) (p < 0.001). In addition, 1q21 amplification by clonal PC occurred at a similar frequency of MM-EMD (33\%), pEMP/SOP (57\%) and classical MM (44\%). Conversely, del(17p13), t(4;14) and t(14;16) were completely absent in pEMP/SOP. Besides this, 1q21 amplification was identified in 64\% of not paraskeletal samples from MM-EMD or pEMP compared to 9\% of SOP or paraskeletal MM-EMD/pEMP and 44\% of classical MM samples, respectively (p = 0.02). Conclusion: Expression of molecules involved in homing and cytogenetic aberrations differ between MM with or without EMD and pEMP/SOP.},
  language  = {en}
}
@article{ZhouRuckdeschelPeteretal.2022,
  author    = {Zhou, Xiang and Ruckdeschel, Anna and Peter, Jessica and B{\"o}ckle, David and Hornburger, Hannah and Danhof, Sophia and Steinhardt, Maximilian Johannes and Heimeshoff, Larissa and Einsele, Hermann and Kort{\"u}m, Klaus Martin and Rasche, Leo},
  title     = {Salvage therapy with "Dara-KDT-P(A)CE" in heavily pretreated, high-risk, proliferative, relapsed/refractory multiple myeloma},
  series = {Hematological Oncology},
  volume    = {40},
  journal   = {Hematological Oncology},
  number    = {2},
  doi       = {10.1002/hon.2949},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257495},
  pages     = {202-211},
  year      = {2022},
  abstract  = {The multi-agent therapy "VDT-PACE" represents an established regimen in relapsed/refractory multiple myeloma (RRMM). Here, we report on our experience with a "modified VDT-PACE" incorporating new generation anti-MM agents daratumumab and carfilzomib ("Dara-KDT-P(A)CE"). We retrospectively analyzed 38 patients with RRMM treated with "Dara-KDT-P(A)CE". The median age was 62 (range 45-82) years, and the patients were heavily pretreated with a median of 5 (range 2-12) prior lines of therapy. Twenty-one (55\%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81\%) patients. The patients received a median of 2 (range 1-10) cycles of this therapy, and the overall response rate (ORR) was 70\%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65\% and 79\%, respectively. The median progression-free survival (PFS) and overall survival were 4.1 (95\% CI 2.7-5.4) and 8.4 (95\% CI 6.7-10.0) months, respectively. Patients with lactate dehydrogenase >250 IU/L showed significantly shorter PFS in comparison with others patients (p = 0.006). We used this regimen as bridging therapy prior to chimeric antigen receptor T-cell infusion in four patients. In conclusion, "Dara-KDT-P(A)CE" is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options.},
  language  = {en}
}
@article{BachmannSchrederEngelhardtetal.2021,
  author    = {Bachmann, Friederike and Schreder, Martin and Engelhardt, Monika and Langer, Christian and Wolleschak, Denise and M{\"u}gge, Lars Olof and D{\"u}rk, Heinz and Sch{\"a}fer-Eckart, Kerstin and Blau, Igor Wolfgang and Gramatzki, Martin and Liebisch, Peter and Grube, Matthias and Metzler, Ivana v. and Bassermann, Florian and Metzner, Bernd and R{\"o}llig, Christoph and Hertenstein, Bernd and Khandanpour, Cyrus and Dechow, Tobias and Hebart, Holger and Jung, Wolfram and Theurich, Sebastian and Maschmeyer, Georg and Salwender, Hans and Hess, Georg and Bittrich, Max and Rasche, Leo and Brioli, Annamaria and Eckardt, Kai-Uwe and Straka, Christian and Held, Swantje and Einsele, Hermann and Knop, Stefan},
  title     = {Kinetics of renal function during induction in newly diagnosed multiple myeloma: results of two prospective studies by the German Myeloma Study Group DSMM},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {6},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13061322},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234139},
  year      = {2021},
  abstract  = {Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3\% at baseline to 1.9\% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49\% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined "renal complete response (CRrenal)" was achieved in 17/25 (68\%) pts after VCD, 12/19 (63\%) after RAD, and 14/27 (52\%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment "renal fitness" in the latter group.},
  language  = {en}
}
@article{ZhouFluechterNickeletal.2020,
  author    = {Zhou, Xiang and Fl{\"u}chter, Patricia and Nickel, Katharina and Meckel, Katharina and Messerschmidt, Janin and B{\"o}ckle, David and Knorz, Sebastian and Steinhardt, Maximilian Johannes and Krummenast, Franziska and Danhof, Sophia and Einsele, Hermann and Kort{\"u}m, K. Martin and Rasche, Leo},
  title     = {Carfilzomib based treatment strategies in the management of relapsed/refractory multiple myeloma with extramedullary disease},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {4},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12041035},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203704},
  year      = {2020},
  abstract  = {Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40-80) years. Twenty (44\%) and 25 (56\%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59\%. Extramedullary response was evaluable in 33 patients, nine (27\%) of them achieved partial remission (PR) (ORR = 27\%). In 15 (33\%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95\% CI, 3.5-6.5) and ten (95\% CI, 7.5-12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients.},
  language  = {en}
}
@article{MoralesLozanoVieringSamnicketal.2020,
  author    = {Morales-Lozano, Maria I. and Viering, Oliver and Samnick, Samuel and Rodriguez-Otero, Paula and Buck, Andreas K. and Marcos-Jubilar, Maria and Rasche, Leo and Prieto, Elena and Kort{\"u}m, K. Martin and San-Miguel, Jesus and Garcia-Velloso, Maria J. and Lapa, Constantin},
  title     = {\(^{18}\)F-FDG and \(^{11}\)C-methionine PET/CT in newly diagnosed multiple myeloma patients: comparison of volume-based PET biomarkers},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {4},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12041042},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203686},
  year      = {2020},
  abstract  = {\(^{11}\)C-methionine (\(^{11}\)C-MET) is a new positron emission tomography (PET) tracer for the assessment of disease activity in multiple myeloma (MM) patients, with preliminary data suggesting higher sensitivity and specificity than \(^{18}\)F-fluorodeoxyglucose (\(^{18}\)F-FDG). However, the value of tumor burden biomarkers has yet to be investigated. Our goals were to corroborate the superiority of \(^{11}\)C-MET for MM staging and to compare its suitability for the assessment of metabolic tumor burden biomarkers in comparison to \(^{18}\)F-FDG. Twenty-two patients with newly diagnosed, treatment-na{\"i}ve symptomatic MM who had undergone \(^{11}\)C-MET and \(^{18}\)F-FDG PET/CT were evaluated. Standardized uptake values (SUV) were determined and compared with total metabolic tumor volume (TMTV) for both tracers: total lesion glycolysis (TLG) and total lesion \(^{11}\)C-MET uptake (TLMU). PET-derived values were compared to Revised International Staging System (R-ISS), cytogenetic, and serologic MM markers such as M component, beta 2 microglobulin (B2M), serum free light chains (FLC), albumin, and lactate dehydrogenase (LDH). In 11 patients (50\%), \(^{11}\)C-MET detected more focal lesions (FL) than FDG (p < 0.01). SUVmax, SUVmean, SUVpeak, TMTV, and TLMU were also significantly higher in \(^{11}\)C-MET than in \(^{18}\)F-FDG (p < 0.05, respectively). \(^{11}\)C-MET PET biomarkers had a better correlation with tumor burden (bone marrow plasma cell infiltration, M component; p < 0.05 versus p = n.s. respectively). This pilot study suggests that \(^{11}\)C-MET PET/CT is a more sensitive marker for the assessment of myeloma tumor burden than \(^{18}\)F-FDG. Its implications for prognosis evaluation need further investigation.},
  language  = {en}
}
@article{SteinhardtZhouKrummenastetal.2020,
  author    = {Steinhardt, Maximilian Johannes and Zhou, Xiang and Krummenast, Franziska and Meckel, Katharina and Nickel, Katharina and B{\"o}ckle, David and Messerschmidt, Janin and Knorz, Sebastian and Dierks, Alexander and Heidemeier, Anke and Lapa, Constantin and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, Klaus Martin},
  title     = {Sequential CD38 monoclonal antibody retreatment leads to deep remission in a patient with relapsed/refractory multiple myeloma},
  series = {International Journal of Immunopathology and Pharmacology},
  volume    = {34},
  journal   = {International Journal of Immunopathology and Pharmacology},
  doi       = {10.1177/2058738420980258},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236235},
  pages     = {1-5},
  year      = {2020},
  abstract  = {We report on a currently 76-year-old female patient with relapsed/refractory (RR) multiple myeloma (MM) treated at our institution. This patient had received six lines of therapy including tandem autologous stem cell transplant, proteasome inhibitor, immunomodulatory drugs and CD38 antibody MOR202. At the last relapse, she progressed during treatment with pomalidomide and MOR202. In an individualized therapy concept, we started a multi-agent salvage therapy with pomalidomide, bortezomib, doxorubicin, dexamethasone, and CD38 antibody daratumumab ("Pom-PAD-Dara"), which resulted in a stringent complete remission with minimal residual disease (MRD) negativity after nine cycles. So far, our patient shows a progression free survival of more than 12 months. Our case demonstrates the feasibility of successful CD38 antibody retreatment in a patient with heavily pretreated CD38 antibody resistant MM.},
  language  = {en}
}
@article{ZhouDierksKertelsetal.2020,
  author    = {Zhou, Xiang and Dierks, Alexander and Kertels, Olivia and Samnick, Samuel and Kircher, Malte and Buck, Andreas K. and Haertle, Larissa and Knorz, Sebastian and B{\"o}ckle, David and Scheller, Lukas and Messerschmidt, Janin and Barakat, Mohammad and Truger, Marietta and Haferlach, Claudia and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, K. Martin and Lapa, Constantin},
  title     = {The link between cytogenetics/genomics and imaging patterns of relapse and progression in patients with relapsed/refractory multiple myeloma: a pilot study utilizing 18F-FDG PET/CT},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {9},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12092399},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211157},
  year      = {2020},
  abstract  = {Utilizing 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT), we performed this pilot study to evaluate the link between cytogenetic/genomic markers and imaging patterns in relapsed/refractory (RR) multiple myeloma (MM). We retrospectively analyzed data of 24 patients with RRMM who were treated at our institution between November 2018 and February 2020. At the last relapse/progression, patients had been treated with a median of three (range 1-10) lines of therapy. Six (25\%) patients showed FDG avid extramedullary disease without adjacency to bone. We observed significantly higher maximum standardized uptake values (SUV\(_{max}\)) in patients harboring del(17p) compared with those without del(17p) (p = 0.025). Moreover, a high SUV\(_{max}\) of >15 indicated significantly shortened progression-free survival (PFS) (p = 0.01) and overall survival (OS) (p = 0.0002). One female patient exhibited biallelic TP53 alteration, i.e., deletion and mutation, in whom an extremely high SUV\(_{max}\) of 37.88 was observed. In summary, this pilot study suggested a link between del(17p)/TP53 alteration and high SUV\(_{max}\) on 18F-FDG PET/CT in RRMM patients. Further investigations are highly warranted at this point.},
  language  = {en}
}
@article{ZhouRascheKortuemetal.2020,
  author    = {Zhou, Xiang and Rasche, Leo and Kort{\"u}m, K. Martin and Danhof, Sophia and Hudecek, Michael and Einsele, Hermann},
  title     = {Toxicities of Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma: An Overview of Experience From Clinical Trials, Pathophysiology, and Management Strategies},
  series = {Frontiers in Immunology},
  volume    = {11},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2020.620312},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219911},
  year      = {2020},
  abstract  = {In the last few years, monoclonal antibodies (mAbs) such as elotuzumab and daratutumab have brought the treatment of multiple myeloma (MM) into the new era of immunotherapy. More recently, chimeric antigen receptor (CAR) modified T cell, a novel cellular immunotherapy, has been developed for treatment of relapsed/refractory (RR) MM, and early phase clinical trials have shown promising efficacy of CAR T cell therapy. Many patients with end stage RRMM regard CAR T cell therapy as their "last chance" and a "hope of cure". However, severe adverse events (AEs) and even toxic death related to CAR T cell therapy have been observed. The management of AEs related to CAR T cell therapy represents a new challenge, as the pathophysiology is not fully understood and there is still no well-established standard of management. With regard to CAR T cell associated toxicities in MM, in this review, we will provide an overview of experience from clinical trials, pathophysiology, and management strategies.},
  language  = {en}
}